We have characterized a mutation affecting the Arabidopsis EARLY IN SHORT DAYS 7 (ESD7) gene encoding the catalytic subunit of the DNA polymerase epsilon (e), AtPOL2A. esd7-1 mutations causes early flowering independently of photoperiod, shortened inflorescence internodes and altered leaf and root development. esd7-1 was a hypomorphic allele whereas KO alleles displayed an embryo-lethal phenotype. The SAM and the RAM in the esd7-1 seedlings were found to exhibit an altered disposition that might correlate with the abnormal expression pattern of SAM and RAM marker genes. esd7-1 showed higher sensitivity to DNA damaging reagents than wild type plants and altered expression of genes involved in DNA repair mechanisms by homologous recombination. Moreover, esd7 early flowering phenotype requires functional FT and SOC1 proteins and might be also related to the mis-regulation of AG and AG-like gene expression found in esd7. Loci involved in the modulation of the chromatin structural dynamics, such as TFL2 and EBS, which negatively regulate FT expression, were found to interact genetically with ESD7, and the carboxy terminus of ESD7 interacted with TFL2 in vitro. Besides, fasciata2 (fas2) mutations suppressed esd7 early flowering phenotype and INCURVATA 2 (ICU2) was found to be epistatic to ESD7. Discrete regions of the chromatin of FT and AG loci were enriched in activating epigenetic marks in the esd7-1 mutant. We concluded that ESD7 might be participating in processes involved in chromatin-mediated cellular memory.
EARLY IN SHORT DAYS 7 (ESD7) encodes the catalytic subunit of DNA polymerase epsilon and is required for flowering repression through a mechanism involving epigenetic gene silencing.
Specimen part
View SamplesIn the central nervous system (CNS), the microRNAs (miRNAs), small endogenous RNAs exerting a negative post-transcriptional regulation on mRNAs, are involved in major functions, such as neurogenesis, and synaptic plasticity. Moreover, they are essential to define the specific transcriptome of the tissues and cell types. However, few studies were performed to determine the miRNome of the different structures of the rat CNS, even through rat is a major model in neuroscience. We determined the miRNome profile of the hippocampus, the cortex, the striatum, the spinal cord and the olfactory bulb, by small RNA-Seq. We found a total of 365 known miRNAs' and 90 novel miRNAs expressed in the CNS of the rat. Novel miRNAs seemed to be important in defining structure-specific miRNomes. Differential analysis showed that several miRNAs were specifically enriched/depleted in these CNS structures. Then, we correlated miRNAs' expression with the expression of their mRNA targets by mRNA-Seq. This analysis suggests that the transcriptomic identity of each structure is regulated by specific miRNAs. Altogether, these results suggest the critical role played by these enriched/depleted miRNAs in the functional identities of CNS structures. Overall design: miRNA and mRNA profile of 5 structures of the central nervous system of rat, for each structurewe analyzed three biological replicates
Small RNA-Seq reveals novel miRNAs shaping the transcriptomic identity of rat brain structures.
Specimen part, Cell line, Subject
View SamplesCombination of GSI with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
Specimen part
View SamplesPrecursor T-cell lymphoblastic neoplasms are aggressive haematological neoplasm that most often manifest with extensive marrow and blood affectation (T-cell acute lymphoblastic leukaemia or T-ALL) or less commonly as a thymic mass with limited bone marrow infiltration (T-cell lymphoblastic lymphoma or T-LBL). Here we show data from RNA-Seq in a sample series of T-LBL from Spanish patients.The goal was to determine the levels of expression of coding genes and microRNAs, and to identify all genetic variants including SNVs, indels, and fusion transcripts. Overall design: Expression data were determined by comparson of each tumour sample with two control thymuses (404 and 405). Genetic variants were determined by comparison of tumour sequences with canonical ENSEMBL normal-references of each gene.
RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas.
Specimen part, Subject
View SamplesIn order to identify putative downstream target genes of RBE, we sequenced mRNA from dexamethasone (DEX) and mock treated transgenic Arabidopsis line 35S:GR-RBE (RBE coding region fused to a glucocorticoid receptor domain driven by the constitutive 35S promoter) floral tissues. We compared the results from DEX and mock treatments and focused on the 832 genes whose expression was significantly reduced (P < 0.025) by 2-fold or more in DEX as compared to mock-treated plants. In this analysis, we identified MIR164c (EEP1) as a candidate target of RBE, which was further confirmed by other molecular and genetic analyses. Regulation of MIR164c by RBE is important for normal floral organ formation in Arabidopsis. Overall design: We used two biological replicates, each with two technical replicates for four hour DEX or mock treated floral tissues to produce 8 sequencing libraries.
RBE controls microRNA164 expression to effect floral organogenesis.
Specimen part, Cell line, Subject
View SamplesTrastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. Some of these patients may become long-term survivors. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression to trastuzumab.
The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy.
Age, Disease
View SamplesHutchinson-Gilford Progeria Syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. We report herein a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. By using this animal model, we have developed an antisense morpholinobased therapy that prevents the pathogenic Lmna splicing, dramatically reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotidebased therapies for treating human diseases of accelerated aging.
Splicing-directed therapy in a new mouse model of human accelerated aging.
Sex, Age, Specimen part
View SamplesFunctional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma, and are thought to be mediated by the plasticity of intact circuits. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators Lppr1 and Lpar1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo Lpar1 inhibition or Lppr1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation. Overall design: GFP labeled Corticospinal motor neurons (CSMNs) were harvetsed via laser capture microdissection to assess gene expression between populations that were quiescent and those that initated a functional axon growth response.
Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury.
Specimen part, Cell line, Subject
View SamplesIn response to acute loss of the Ulp2 SUMO-specific protease, yeast become disomic for chromosome I (ChrI) and ChrXII. Here we report that ChrI disomy, which creates an adaptive advantage in part by increasing the dosage of the Ccr4 deadenylase, was eliminated by extended passaging. Loss of aneuploidy is often accompanied by mutations in essential SUMO-ligating enzymes, which reduced polySUMO-conjugate accumulation. The mRNA levels for almost all ribosomal proteins increases transiently upon initial loss of Ulp2, but elevated Ccr4 levels limit excess ribosome formation. Notably, extended passaging leads to increased levels of many small nucleolar RNAs (snoRNAs) involved in ribosome biogenesis, and higher dosage of three linked ChrXII snoRNA genes suppressed ChrXII disomy in ulp2? cells. Our data reveal that aneuploidy allows rapid adaptation to Ulp2 loss, but long-term adaptation restores euploidy. Cellular evolution restores homeostasis through countervailing mutations in SUMO-modification pathways and regulatory shifts in ribosome biogenesis. Overall design: In these comparisons, the ulp2? cells either carried a WT ULP2 plasmid or empty vector and were passaged for 50 or 500 generations. mRNA profiles of them were generated by sequencing, in triplicate, using Illumina HiSeq 2500 .
Distinct adaptive mechanisms drive recovery from aneuploidy caused by loss of the Ulp2 SUMO protease.
Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Estrogen receptor subtype beta2 is involved in neuromast development in zebrafish (Danio rerio) larvae.
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